Abstract Clostridium difficile is the most frequent bacterial cause of antibiotic-associated diarrhea. Solid organ transplant recipients have a higher rate of C. difficile infection (CDI), and greater risk for adverse consequences because of immunosuppression, frequent antibiotic use and medical procedures all of which disrupt the normal gut microbiota. Dysbiosis of the gut microbiota predisposes to CDI which, despite treatment can recur in 30% of patients. A novel way to prevent CDI recurrence is by instilling feces from a healthy individual into the intestine of the CDI patient, thereby restoring balance in the gut microbiota. However, it is unknown whether or not fecal microbiota transplantation (FMT) is an efficacious choice for CDI recurrence prevention in SOT recipients. We propose a randomized, double-blind double-dummy placebo-controlled trial at five sites comparing FMT with oral vancomycin for 158 SOT recipients with at least a first but no more than 3 recurrences of CDI. We will collect fecal and blood samples from subjects prior to and after FMT and collect data on recurrence, CDI-related quality of life, microbiota composition and function. The trial's primary endpoint is recurrent CDI in the 60-day time frame following completion of treatment. Secondary outcomes are safety and gut microbiota characteristics. Each subject will contribute 6 stool samples, 3 blood samples and will have 6 clinic visits. Total duration of follow-up will be 24 weeks per subject. The FMT will be administered via enema using frozen stool from universal donors. By following patients for 6 months, we will determine whether FMT successfully and safely reduces recurrence of CDI and improves other outcomes in SOT recipients with CDI.